Scientists from The Johns Hopkins University School of Medicine and elsewhere
have found the brain's "nose plug" - the switch in the brain that
lets us stop smelling something, even though the odor is still there.

"The ability to desensitize to odors is important for our well-being,"
says Randall Reed, Ph.D., a Howard Hughes Medical Institute (HHMI) investigator
and a molecular biologist and neuroscientist in the school's Institute for Basic
Biomedical Sciences. "Odor adaptation is important in telling whether a
scent is getting stronger or going away, and it prevents sensory overload. Understanding
this process should help us figure out how adaptation affects our perception
of odors."

Two papers published in the Dec. 7 issue of Science show that a protein called
CNGA4 helps plug the "nose" of odor receptor cells -- neurons whose
job is to detect smells and send that information to the brain as an electrical
signal. The "nose" is really a channel in the neurons' membrane that
opens when an odor is presented and closes as the neuron becomes desensitized
to that smell.

By measuring the signals from these odor receptor cells in genetically engineered
mice, Reed and his colleagues showed that mice lacking CNGA4 can't adapt to
odors. Other scientists studied the molecule's behavior in laboratory-grown
cells and reported that CNGA4 speeds up the "nose's" closing.

In normal mice, and in humans, the electrical signal from odor receptor neurons
diminishes quickly over time, even when the odor is still present. Also, the
neurons usually produce a much smaller electrical signal if exposed to the same
odor twice in a short period of time, says Reed.

Using mice that were missing CNGA4, a protein they thought to be involved in
odor sensitivity, Reed and his collaborators from the University of Maryland,
Baltimore, found that mice without CNGA4 could sense odors but could not adapt
to them. In these mice, the signal from the neurons stayed almost constant,
and the response to an odor the second time was identical to that from the initial
exposure.

"Adaptation and sensitivity are related, but CNGA4 clearly plays a bigger
role in adaptation," says Reed. "We thought we knew what the protein
did, but the gene knockout mouse showed us that we didn't. It showed us that
the biggest impact of CNGA4 is on odor adaptation, not sensitivity."

In a separate study, Jonathan Bradley, a postdoctoral fellow in neuroscience
in HHMI at Johns Hopkins, examined the electrical behavior of CNGA4 and the
odor channel in isolated cells. The channel opens in response to one molecule
(cAMP), letting charged calcium atoms inside the odor neuron. The channel closes
as the calcium entering the cell turns around and inhibits it.

Bradley's experiments revealed that when CNGA4 is present, the odor channel
closes within one second of opening. Without CNGA4, it takes 100 times longer
for enough calcium to bind and close the channel, he reports.

"We came by CNGA4's involvement by our interest in what the channel is
doing from a biology perspective, and they came at it from the biophysical side,"
says Reed. "It's really nice because we can refer to their detailed work
about the mechanism, and they can refer to ours because we have generated the
protein's biological effects. This is what science is about."

The scientists are now evaluating how the lack of CNGA4 affects the mouse's
normal behavior and how exactly CNGA4 facilitates calcium binding, Reed says.

Co-authors with Reed are Steven Munger, formerly of Hopkins and now at the
University of Maryland, Baltimore; Andrew Lane, Trese Leinders-Zufall and Frank
Zufall of the University of Maryland, Baltimore; and Haining Zhong and King-Wai
Yau of Johns Hopkins (Science, 294:2172-2175). Funding was provided by the Howard
Hughes Medical Institute, the National Institute on Deafness and Other Communication
Disorders, the National Institute of Neurological Disorders and Stroke, and
the National Science Foundation.

Co-authors with Bradley, who was at the Ecole Normale Superiere in Paris,
are Dirk Reuter, now with Sophion Bioscience in Denmark, and Stephan Frings
of the Institute for Biological Information Processing in Juelich, Germany (Science,
294:2176-2178). Funding was provided by the Deutsche Forschungsgemeinschaft
(German Research Partnership), European Community and the Centre Nationale de
la Recherche Scientifique (CNRS, National Center for Scientific Research).